Signal transducers and activator of transcription 3 (STAT3) is frequently activated in human cancers and aberrant activation of STAT3 signaling is involved in tumor initiation, progression, drug resistance and immune evasion. Thus, STAT3 has been considered to be a highly attractive cancer therapeutic target. However, discovery and development of highly potent and selective small-molecule inhibitors of STAT3 have proven to be very challenging for a number of reasons. The proteolysis targeting chimera (PROTAC) strategy has recently gained tremendous momentum for its promise for the discovery and development of an entirely different type of new therapeutics through inducing targeted protein degradation. We hypothesize that PROTAC STAT3 degraders (hereafter called STAT3 degraders) may be much more effective than STAT3 inhibitors in inhibition of STAT3 transcriptional activity. To date, no STAT3 degraders have been reported. Based upon a class of highly potent STAT3 inhibitors, we have designed and developed the first-in-class STAT3 degraders, as exemplified by our lead compound SD-36. SD-36 is highly potent and effective in inducing the degradation of STAT3 protein and demonstrates an absolute selectivity over other STAT members and all other >5,000 proteins examined. Degradation of STAT3 by SD-36 results in a robust suppression of STAT3 transcription activity and down-regulation of STAT3 transcription network in tumor cells. Our initial screening demonstrated that SD-36 inhibits the growth of a subset of AML and ALCL cell lines that express high levels of p-STAT3 (Y705). Our pharmacodynamic (PD) studies showed that a single intravenous administration of SD-36 is capable of reducing STAT3 protein by >90%, with the effect persisted for more than 3 days. SD-36 achieves complete tumor regression in multiple xenograft models in mice at well tolerate doss-schedules. Our data demonstrate that degradation of STAT3 protein is a highly promising cancer therapeutic strategy. Based upon our compelling preliminary data, we propose to design, synthesize and develop highly potent small-molecule STAT3 degraders as a new class of therapies for the treatment of human cancer and to elucidate their mechanism of action. In addition to performance of extensive evaluations of SD-36 in vitro and in vivo, we will further optimize SD-36 for potency and efficacy and address any weaknesses we uncover for SD-36. Our goal is to select one or more highly potent and optimized STAT3 degrader for advanced preclinical development for the treatment of human cancers with activated STAT3.